Recombinant pro-apoptotic Mycobacterium tuberculosis generates CD8+ T cell responses against human immunodeficiency virus type 1 Env and M. tuberculosis in neonatal mice

Uma Devi K Ranganathan, Michelle H. Larsen, John Kim, Steven A. Porcelli, William R. Jacobs, Glenn J. Fennelly

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22 Citations (Scopus)

Abstract

Mycobacterium bovis BCG is an attractive vaccine vector against breast milk HIV transmission because it elicits Th1-type responses in newborns. However, BCG causes disease in HIV-infected infants. Genetically attenuated Mycobacterium tuberculosis (Mtb) mutants represent a safer alternative for immunocompromised populations. In the current study, we compared the immunogenicity in mice of three different recombinant attenuated Mtb strains expressing an HIV envelope (Env) antigen construct. Two of these strains (ΔlysA ΔpanCD Mtb and ΔRD1 ΔpanCD Mtb) failed to induce significant levels of HIV Env-specific CD8+ T cell responses. In striking contrast, an HIV-1 Env-expressing attenuated ΔlysA Mtb containing a deletion in secA2, which encodes a virulence-related secretion system involved in evading adaptive immunity, generated consistently measurable Env-specific CD8+ T cell responses that were significantly greater than those observed after immunization with BCG expressing HIV Env. Similarly, another strain of ΔlysA ΔsecA2 Mtb expressing SIV Gag induced Gag- and Mtb-specific CD8+ T cells producing perforin or IFNγ, and Gag-specific CD4+ T cells producing IFNγ within 3 weeks after immunization in adult mice; in addition, IFNγ-producing Gag-specific CD8+ T cells and Mtb-specific CD4+ T cells were observed in neonatal mice within 1 week of immunization. We conclude that ΔlysA ΔsecA2 Mtb is a promising vaccine platform to construct a safe combination HIV-TB vaccine for use in neonates.

Original languageEnglish (US)
Pages (from-to)152-161
Number of pages10
JournalVaccine
Volume28
Issue number1
DOIs
StatePublished - Dec 10 2009

Fingerprint

Mycobacterium tuberculosis
Human immunodeficiency virus 1
HIV-1
neonates
T-lymphocytes
T-Lymphocytes
Mycobacterium bovis
HIV
Immunization
immunization
Vaccines
HIV Antigens
Newborn Infant
vaccines
immunocompromised population
Combined Vaccines
Mycobacterium bovis BCG
vector vaccines
AIDS Vaccines
Perforin

Keywords

  • Attenuated M. tuberculosis
  • CD8 T cell immunogen
  • Combination HIV-TB vaccine
  • HIV-1 Env
  • Neonatal vaccines

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • veterinary(all)
  • Molecular Medicine

Cite this

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title = "Recombinant pro-apoptotic Mycobacterium tuberculosis generates CD8+ T cell responses against human immunodeficiency virus type 1 Env and M. tuberculosis in neonatal mice",
abstract = "Mycobacterium bovis BCG is an attractive vaccine vector against breast milk HIV transmission because it elicits Th1-type responses in newborns. However, BCG causes disease in HIV-infected infants. Genetically attenuated Mycobacterium tuberculosis (Mtb) mutants represent a safer alternative for immunocompromised populations. In the current study, we compared the immunogenicity in mice of three different recombinant attenuated Mtb strains expressing an HIV envelope (Env) antigen construct. Two of these strains (ΔlysA ΔpanCD Mtb and ΔRD1 ΔpanCD Mtb) failed to induce significant levels of HIV Env-specific CD8+ T cell responses. In striking contrast, an HIV-1 Env-expressing attenuated ΔlysA Mtb containing a deletion in secA2, which encodes a virulence-related secretion system involved in evading adaptive immunity, generated consistently measurable Env-specific CD8+ T cell responses that were significantly greater than those observed after immunization with BCG expressing HIV Env. Similarly, another strain of ΔlysA ΔsecA2 Mtb expressing SIV Gag induced Gag- and Mtb-specific CD8+ T cells producing perforin or IFNγ, and Gag-specific CD4+ T cells producing IFNγ within 3 weeks after immunization in adult mice; in addition, IFNγ-producing Gag-specific CD8+ T cells and Mtb-specific CD4+ T cells were observed in neonatal mice within 1 week of immunization. We conclude that ΔlysA ΔsecA2 Mtb is a promising vaccine platform to construct a safe combination HIV-TB vaccine for use in neonates.",
keywords = "Attenuated M. tuberculosis, CD8 T cell immunogen, Combination HIV-TB vaccine, HIV-1 Env, Neonatal vaccines",
author = "Ranganathan, {Uma Devi K} and Larsen, {Michelle H.} and John Kim and Porcelli, {Steven A.} and Jacobs, {William R.} and Fennelly, {Glenn J.}",
year = "2009",
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T1 - Recombinant pro-apoptotic Mycobacterium tuberculosis generates CD8+ T cell responses against human immunodeficiency virus type 1 Env and M. tuberculosis in neonatal mice

AU - Ranganathan, Uma Devi K

AU - Larsen, Michelle H.

AU - Kim, John

AU - Porcelli, Steven A.

AU - Jacobs, William R.

AU - Fennelly, Glenn J.

PY - 2009/12/10

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N2 - Mycobacterium bovis BCG is an attractive vaccine vector against breast milk HIV transmission because it elicits Th1-type responses in newborns. However, BCG causes disease in HIV-infected infants. Genetically attenuated Mycobacterium tuberculosis (Mtb) mutants represent a safer alternative for immunocompromised populations. In the current study, we compared the immunogenicity in mice of three different recombinant attenuated Mtb strains expressing an HIV envelope (Env) antigen construct. Two of these strains (ΔlysA ΔpanCD Mtb and ΔRD1 ΔpanCD Mtb) failed to induce significant levels of HIV Env-specific CD8+ T cell responses. In striking contrast, an HIV-1 Env-expressing attenuated ΔlysA Mtb containing a deletion in secA2, which encodes a virulence-related secretion system involved in evading adaptive immunity, generated consistently measurable Env-specific CD8+ T cell responses that were significantly greater than those observed after immunization with BCG expressing HIV Env. Similarly, another strain of ΔlysA ΔsecA2 Mtb expressing SIV Gag induced Gag- and Mtb-specific CD8+ T cells producing perforin or IFNγ, and Gag-specific CD4+ T cells producing IFNγ within 3 weeks after immunization in adult mice; in addition, IFNγ-producing Gag-specific CD8+ T cells and Mtb-specific CD4+ T cells were observed in neonatal mice within 1 week of immunization. We conclude that ΔlysA ΔsecA2 Mtb is a promising vaccine platform to construct a safe combination HIV-TB vaccine for use in neonates.

AB - Mycobacterium bovis BCG is an attractive vaccine vector against breast milk HIV transmission because it elicits Th1-type responses in newborns. However, BCG causes disease in HIV-infected infants. Genetically attenuated Mycobacterium tuberculosis (Mtb) mutants represent a safer alternative for immunocompromised populations. In the current study, we compared the immunogenicity in mice of three different recombinant attenuated Mtb strains expressing an HIV envelope (Env) antigen construct. Two of these strains (ΔlysA ΔpanCD Mtb and ΔRD1 ΔpanCD Mtb) failed to induce significant levels of HIV Env-specific CD8+ T cell responses. In striking contrast, an HIV-1 Env-expressing attenuated ΔlysA Mtb containing a deletion in secA2, which encodes a virulence-related secretion system involved in evading adaptive immunity, generated consistently measurable Env-specific CD8+ T cell responses that were significantly greater than those observed after immunization with BCG expressing HIV Env. Similarly, another strain of ΔlysA ΔsecA2 Mtb expressing SIV Gag induced Gag- and Mtb-specific CD8+ T cells producing perforin or IFNγ, and Gag-specific CD4+ T cells producing IFNγ within 3 weeks after immunization in adult mice; in addition, IFNγ-producing Gag-specific CD8+ T cells and Mtb-specific CD4+ T cells were observed in neonatal mice within 1 week of immunization. We conclude that ΔlysA ΔsecA2 Mtb is a promising vaccine platform to construct a safe combination HIV-TB vaccine for use in neonates.

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